Loss of TP73 function contributes to amyotrophic lateral sclerosis pathogenesis

BioRxiv : the Preprint Server for Biology
Jonathan M DownieLynn B Jorde

Abstract

Much remains unknown about the genetics and pathophysiology underlying the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We analyzed exome sequences from a cohort of 87 sporadic ALS (SALS) patients and 324 healthy individuals. TP73, a homolog of the TP53 tumor suppressor gene, had five rare deleterious protein-coding variants; in a separate collection of >2,900 ALS patients we identified an additional 19 rare deleterious variants in TP73. An in vitro C2C12 myoblast growth assay confirmed that these variants impair or alter TP73 function. In vivo mutagenesis of zebrafish tp73 using CRISPR led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology. Together, these results demonstrate that TP73 is a risk factor for ALS, and identifies a novel dysfunctional cellular process in the pathogenesis of ALS.

Related Concepts

Amyotrophic Lateral Sclerosis
Motor Neurons
Pathology
Physiological Aspects
Zebrafish
Tumor Suppressor Genes
Mutagenesis Process
Myoblasts
Cohort
Pathogenesis

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